Cholesteryl Ester Storage Disease Clinical Trials

• Age 12 months to 18 years (infantile form is out of scope for the analytical component);

• Patients not previously evaluated for LAL-D (test-naïve);

• Presence of at least one (1) of the following major criteria:

• Unexplained hepatomegaly and/or splenomegaly persisting ≥3 months;

• Persistent hypertransaminasemia: ALT or AST ≥ 1.5× upper limit of normal (ULN) after exclusion of common metabolic/infectious causes;

• Atherogenic dyslipidemia: elevated total cholesterol (TC), elevated LDL-C and/or reduced HDL-C (LDL-C \>95th percentile for age and sex or HDL-C \<5th percentile); triglycerides not markedly elevated.

• Presence of at least two (2) of the following minor criteria:

• Chronic diarrhea or intermittent unstable bowel movements;

• Abdominal pain and/or bloating;

• Loss of appetite;

• Nausea, vomiting;

• Belching, heartburn;

• Weight loss, growth deceleration (height/weight lag behind peers);

• Weakness, easy fatigability;

• Recurrent aphthous stomatitis (oral mucosal ulcers);

• Splenomegaly (if not counted as a major criterion);

• Anemia and/or thrombocytopenia;

• Evidence of steatosis/fibrosis by ultrasound/elastography/ liver examination by MRI;

• Suboptimal response to lipid-lowering therapy: after ≥3 months of optimized therapy (maximally tolerated statin ± ezetimibe with documented adherence), LDL-C reduction \<50% from baseline OR on-treatment LDL-C remains above guideline targets (e.g., ≥3.4 mmol/L without very high risk or ≥2.6 mmol/L in very-high-risk settings), despite therapy \[12\].

• Family history of FH-like dyslipidemia without typical FH genetic markers (if available).

• Provision of signed and dated written informed consent by parent(s)/legal guardian(s) (and the child, where applicable).